The microcirculation of the renal medulla traps NaCl and urea to facilitate urinary concentration and supplies metabolites to mitigate hypoxia. Descending vasa recta (DVR) are 15 mm diameter arteriolar microvessels that supply all blood flow to the medulla. Through contraction of abluminal smooth muscle / pericytes, DVR regulate medullary perfusion. We have established methods to study contraction, Ca2+ signaling and ion channel architecture of the pericytes. Depolarization of pericyte membrane potential opens voltage gated cation entry channels that conduct Na+ (NaV) or Ca2+ (CaV). In turn, depolarization occurs through a combination of Ca2+ dependent Cl- channel (CaCC) activation and K+ channel inhibition. We provide evidence that DVR cation conductance is heavily regulated by NO and heme oxygenase (HO) and that it is modified in Dahl salt sensitive rats and eNOS null mice. We will study the regulation of DVR pericyte CaV by intrinsic activity of nitric oxide synthase (NOS) and HO in normal and hypertensive rodent models. Aim 1 will test the regulation of DVR pericyte CaV by nitric oxide synthase (NOS) and NO. We will identify which CaV subclasses are suppressed by NO and which NOS isoforms generate NO in the DVR wall of rats and eNOS / nNOS null mice. The relevant signaling pathways involved will be delineated. Finally, a role for the DVR NaV conductance will be studied with respect to its operation in Ca2+ conducting slip mode or in concert with Na+/Ca2+ exchange. Aim 2 will study the regulation of DVR pericyte CaV by heme oxygenase / CO. We will test the ability of HO activation and suppression to modify CaV conductance, membrane potential and vessel contraction. We will employ methods to upregulate and reduce expression of HO- 1 in vivo to test the consequences on DVR channel activity and contractility. Aim 3 will examine alteration of pericyte voltage gated Ca2+ entry pathways in salt sensitive hypertension. We will determine which channel conductances account for the depolarized state of Dahl/SS pericytes. We will measure rates of NO generation and study the consequences of supplying L-arginine, a maneuver known to reverse paucity of medullary NO generation. We will test whether upregulation of HO-1 normalizes CaV conductance and membrane potential in Dahl/SS rats and examine the ability of intramedullary CaV blockade to augment perfusion of the medulla in those animals.